This is one of a trilogy of applications with a common theme. They concern the synthesis, testing in vitro and in vivo and the evaluation of mechanisms of action of a generation of bio- reductive anti-cancer drugs that can function as hypoxic sensitizers, as differential cytotoxic agents of oxygen-deficient cells in tumors and as potentiators of other anti-cancer drugs. These compounds are based on the principles of 'dual function' shown by the lead compound RSU 1069, a 2-nitroimidazole containing an aziridine function in the 1-subtituted side chain. This compound gives rise to substantial radiation- and chemo- sensitization at doses an order of magnitude less than those required for misonidazole. Further, the differential toxicity towards hypoxic cells is extremely high showing the potential of this class of compound for use as anti-cancer drugs activated bio- reductively. The basic rationale for this collaborative program is to synthesize new compounds of this type, examine their effectiveness as radiation sensitizers, chemo-sensitizers and differential cytotoxic agents for oxygen-deficient cells in a variety of cell lines in culture, in multi-cellular spheroids and in experimental tumors of different types that are already established in the applicants laboratories. In addition, mechanistic studies will include investigation of structure activity relationships since it has already been shown that chemical modifications of RSU 1069 and similar types of compounds can profoundly affect cytotoxicity both in vitro and in vivo without greatly influencing sensitizing ability. For RSU 1069, the high differential hypoxic cytotoxicity is due to its conversion to a highly reactive bifunctional agent by anaerobic reduction. This leads to an increase in strand breakage and cross-linking in DNA. However, RSU 1069 which is also considerably more toxic than misonidazole to aerobic cells, causes oncogenic transformation in unirradiated C3H 10T1/2 and Balb 3T3 cells. An important part of the combined programme will be to examine therefore the transforming ability of the new compounds in a structure-activity study. This will be aimed at assessing the importance of factors such as electron-affinity, the degree of activation of the aziridinel group and other mono-functional alkylating moieties, lipophilic properties and relationships, if any, between transforming ability, aerobic and hypoxic cytotoxicity and radiation-sensitizing effectiveness.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA044128-02
Application #
3186691
Study Section
Radiation Study Section (RAD)
Project Start
1987-09-30
Project End
1990-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Hei, T K; Piao, C Q; He, Z Y et al. (1992) Mechanism of oncogenicity for bioreductive drugs. Int J Radiat Oncol Biol Phys 22:747-50
Hall, E J; Hei, T K (1992) Oncogenic transforming potential of etanidazole. Int J Radiat Oncol Biol Phys 22:743-5
Weinberg, R S; Leibowitz, D; Weinblatt, M E et al. (1990) Juvenile chronic myelogenous leukaemia: the only example of truly fetal (not fetal-like) erythropoiesis. Br J Haematol 76:307-10
Hei, T K; He, Z Y; Piao, C Q et al. (1990) Studies with bifunctional bioreductive drugs. I. In vitro oncogenic transforming potential. Radiat Res 124:S44-9
Roizin-Towle, L; Pirro, J P; Hall, E J (1990) Studies with bifunctional bioreductive drugs. II. Cytotoxicity assayed with A-549 lung carcinoma cells of human origin. Radiat Res 124:S50-5
Lutzky, J; Astor, M B; Taub, R N et al. (1989) Role of glutathione and dependent enzymes in anthracycline-resistant HL60/AR cells. Cancer Res 49:4120-5
Hall, E J; Hei, T K (1989) Oncogenic transforming potential of nitroimidazole radiosensitizers. Int J Radiat Oncol Biol Phys 16:1231-4